Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

The efficacy of medical treatment in patients with acromegaly in clinical practice.

Although somatostatin analogues (SSAs) are recommended as the first-line medical therapy for acromegaly, dopamine agonists (DAs) are also a therapeutic option for treatment. We aimed to assess and compare the efficacies of DAs and SSAs in treating acromegaly in clinical practice. We included 89 patients with acromegaly who took DAs (bromocriptine [BCT], n = 63; cabergoline [CAB], n = 11) or SSAs (n = 15) as a primary medical therapy for more than 3 months in the Seoul National University Hospital. The CAB (45.5%) and SSA (33.3%) groups achieved random GH levels of <2.5 ng/mL and the normal IGF-1 levels were significantly higher than in the BCT group (11.1%) (p = 0.009). We further included all the patients with acromegaly (n = 132) who had taken CAB, BCT, and SSAs as first- or second-line medical therapy. The CAB group showed similar efficacy as the SSA group in terms of the GH and insulin-like growth factor-1 (IGF-1) levels (57.6% for random GH level <2.5 ng/mL, 42.4% for normal IGF-1 levels, 36.4% for both). Logistic regression analysis revealed that medications, age, GH level, or IGF-1 level before medication, hyperprolactinemia, and prior gamma-knife surgery or radiation therapy, did not affect the therapeutic response. High pretreatment GH levels predicted poor treatment outcomes (odds ratio [95% confidence interval] = 0.95 [0.90-0.99]). CAB was effective in treating acromegaly at a relatively lower cost in patients with low pretreatment GH levels.

The assessment of total antioxidant capacity and superoxide dismutase levels, and the possible role of manganese superoxide dismutase polymorphism in acromegaly.

Oxidative status is attributed to endothelial dysfunction and might be one of the key mechanisms of endothelial dysfunction in acromegaly. In this study, we aimed to investigate the effect of acromegaly on superoxide dismutase (SOD) and total antioxidant capacity (TAC) levels, and the possible influence of human manganese superoxide dismutase (MnSOD) polymorphism on these levels. 51 acromegaly patients and 57 age and sex matched healthy subjects were recruited to the study in Bezmialem Vakif University Hospital between 2011 and 2014. The median SOD and TAC levels were 42.7 (33-60) pg/mL and 1,313.7 (155-1,902) µM in acromegaly; and 46.3 (38-95) pg/mL and 1,607.3 (195-1,981) µM in healthy subjects (p < 0.001, p < 0.001). SOD levels were decreased in controlled and uncontrolled patients compared to healthy subjects (p = 0.05 and p = 0.002, respectively). Controlled and uncontrolled acromegaly displayed significantly decreased levels of TAC compared to healthy subjects (p < 0.05 and p < 0.001, respectively). SOD levels were not associated with MnSOD polymorphisms in acromegaly. In conclusion, this study showed that acromegaly was associated with decreased levels of SOD and TAC, and controlling the disease activity could not adequately improve these levels.

The Mexican Acromegaly Registry: Clinical and Biochemical Characteristics at Diagnosis and Therapeutic Outcomes.

CONTEXT: Acromegaly is a systemic disorder caused by a GH-secreting pituitary adenoma. As with other rare diseases, acromegaly registries developed in various European countries have provided us with important information. OBJECTIVE: The objective of the study was to analyze the epidemiological, clinical, biochemical, and therapeutic data from the Mexican Acromegaly Registry (MAR). SETTING: The setting of the study was a nationwide patient registry. DESIGN AND METHODOLOGY: The MAR was created in 2009. It gathers data from 24 participating centers belonging to three different institutions using a specifically designed on-line platform. Only patients diagnosed after 1990 were included in the program. RESULTS: A total of 2057 patients (51% female, mean age at diagnosis 41.1 ± 24.5 y) have been registered for an estimated prevalence of 18 cases per 1 million inhabitants. Hypertension, glucose intolerance, diabetes, and dyslipidemia were present in 27%, 18.4%, 30%, and 24% of the patients, respectively. The IGF-1 level at diagnosis and the concomitant presence of hypertension were significantly associated with the development of diabetes. Transsphenoidal surgery was the primary treatment in 72% of the patients. Pharmacological treatment, mostly with somatostatin analogs, was administered primarily and adjunctively in 26% and 54% of the patients, respectively. Treatment choice varied among the three participating institutions, with the predominance of pharmacological therapy in two of them and of radiation therapy in the third. Therapeutic outcomes were similar to those reported in the European registries. CONCLUSIONS: The MAR is the largest and first non-European registry of the disease. Our findings highlight important within-country differences in treatment choice due to variations in the availability of resources.

Patients lost to follow-up in acromegaly: results of the ACROSPECT study.

OBJECTIVE: The complex management of acromegaly has transformed this disease into a chronic condition, with the risk of patients being lost to follow-up. The objective of this study was to estimate the proportion of acromegalic patients lost to follow-up in France and to determine the impact that abandoning follow-up has on the disease and its management. DESIGN: ACROSPECT was a French national, multicentre, cross-sectional, observational study. METHODS: Acromegalic patients were considered lost to follow-up if no new information had been entered in their hospital records during the previous 2 years. They were traced where possible, and data were collected by means of a recall visit or questionnaire. RESULTS: In the study population, 21% of the 2392 acromegalic patients initially followed in 25 tertiary endocrinology centres were lost to follow-up. At their last follow-up visit, 30% were uncontrolled, 33% were receiving medical therapy and 53% had residual tumour. Of the 362 traced, 62 had died and 77% were receiving follow-up elsewhere; the leading reason for abandoning follow-up was that they had not been informed that it was necessary. Our analysis of the questionnaires suggests that they were not receiving optimal follow-up. CONCLUSIONS: This study underlines the need to better inform acromegalic patients of the need for long-term follow-up, the absence of which could be detrimental to patients' health, and to develop shared care for what must now be regarded as a chronic disease.

Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study.

BACKGROUND: In active acromegaly, pathologically elevated GH and IGF-1 levels are associated with increased bone turnover and a high bone mass, the latter being sustained after normalization of GH values. In a cross-sectional study design, we have previously reported a high prevalence of vertebral fractures (VFs) of about 60% in patients with controlled acromegaly, despite normal mean bone mineral density (BMD) values. Whether these fractures occur during the active acromegaly phase or after remission is achieved is not known. OBJECTIVE: Our objective was to study the natural progression of VFs and contributing risk factors in patients with controlled acromegaly over a 2.5-year follow-up period. METHODS: Forty-nine patients (mean age 61.3 ± 11.1 years, 37% female) with controlled acromegaly for ≥ 2 years after surgery, irradiation, and/or medical therapy and not using bisphosphonates were included in the study. Conventional spine radiographs including vertebrae Th4-L4 were assessed for VFs according to the Genant method. VF progression was defined as development of new/incident fractures and/or a minimum 1-point increase in the Genant scoring of preexisting VFs. BMD was assessed by dual-energy x-ray absorptiometry (Hologic 4500). RESULTS: Prevalence of baseline VFs was 63%, being highest in men, and fractures were unrelated to baseline BMD. VF progression was documented in 20% of patients, especially in men and in case of ≥ 2 VFs at baseline. VF progression was not related to BMD values or BMD changes over time. CONCLUSION: Findings from this longitudinal study show that VFs progress in the long term in 20% of patients with biochemically controlled acromegaly in the absence of osteoporosis or osteopenia. These data suggest that an abnormal bone quality persists in these patients after remission, possibly related to pretreatment long-term exposure to high circulating levels of GH.

Characterization of SNARE proteins in human pituitary adenomas: targeted secretion inhibitors as a new strategy for the treatment of acromegaly?

CONTEXT: Targeted secretion inhibitors (TSIs), a new class of recombinant biotherapeutic proteins engineered from botulinum toxin, represent a novel approach for treating diseases with excess secretion. They inhibit hormone secretion from targeted cell types through cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) proteins. qGHRH-LH(N)/D is a TSI targeting pituitary somatotroph through binding to the GHRH-receptor and cleavage of the vesicle-associated membrane protein (VAMP) family of SNARE proteins. OBJECTIVE: Our objective was to study SNARE protein expression in pituitary adenomas and to inhibit GH secretion from somatotropinomas using qGHRH-LH(N)/D. DESIGN: We analyzed human pituitary adenoma analysis for SNARE expression and response to qGHRH-LH(N)/D treatment. SETTING: The study was conducted in University Hospitals. PATIENTS: We used pituitary adenoma samples from 25 acromegaly and 47 nonfunctioning pituitary adenoma patients. OUTCOME: Vesicle-SNARE (VAMP1-3), target-SNARE (syntaxin1, SNAP-23, and SNAP-25), and GHRH-receptor detection with RT-qPCR, immunocytochemistry, and immunoblotting. Assessment of TSI catalytic activity on VAMPs and release of GH from adenoma cells. RESULTS: SNARE proteins were variably expressed in pituitary samples. In vitro evidence using recombinant GFP-VAMP2&3 or pituitary adenoma lysates suggested sufficient catalytic activity of qGHRH-LH(N)/D to degrade VAMPs, but was unable to inhibit GH secretion in somatotropinoma cell cultures. CONCLUSIONS: SNARE proteins are present in human pituitary somatotroph adenomas that can be targeted by TSIs to inhibit GH secretion. qGHRH-LH(N)/D was unable to inhibit GH secretion from human somatotroph adenoma cells. Further studies are required to understand how the SNARE proteins drive GH secretion in human somatotrophs to allow the development of novel TSIs with a potential therapeutic benefit.

Factors influencing the outcome of microsurgical transsphenoidal surgery for pituitary adenomas: a study on 184 patients.

OBJECTIVE: Evaluation of factors influencing the outcome of microsurgical transsphenoidal surgery in patients harbouring pituitary adenomas as well as of the efficacy and safety of this procedure. DESIGN: A total of 184 consecutive patients with pituitary adenomas, undergoing microsurgical transsphenoidal resection of their lesions from March 2004 to June 2011, were prospectively studied. Extent of tumour resection and disease remission were defined according to recently established radiological and hormonal consensus criteria. RESULTS: The study included 97 nonfunctioning and 87 functioning adenomas. A gross-total removal, as documented on postoperative imaging, was achieved in 67.4% of all patients. Residual tumour after surgery was detected in 37.1% of patients with nonfunctioning adenomas. The remission rates for patients with functioning adenomas, as documented by the last endocrinological evaluation, were 54.9% for growth hormone-secreting, 69.5% for adrenocorticotropin hormone-secreting, 72.7% for prolactin-secreting and 100% for thyroid-stimulating hormone-secreting, with two recurrences in patients with Cushing's disease. Multivariate analysis showed that factors influencing surgical outcome were cavernous sinus invasion, large tumour diameter (≥25 mm) and reoperation for the nonfunctioning adenomas, and cavernous sinus invasion as well as large tumour diameter (≥25 mm) for the functioning adenomas. In the latter cohort, predictors for endocrinological remission were maximum tumour diameter (≤20 mm) and reoperation. Postoperative complications were present in 3.3% of the cases. One patient developed epistaxis, two hemorrhage at the surgical field, one postoperative rhinorrhea, one postoperative permanent diabetes insipidus and one postoperative panhypopituitarism. CONCLUSIONS: Microsurgical transsphenoidal surgery is an effective and safe treatment in all patients with pituitary adenomas, except for prolactinomas responsive to medical therapy.

Efficacy of combined octreotide and cabergoline treatment in patients with acromegaly: a retrospective clinical study and review of the literature.

Although somatostatin analogues are effective medical therapy for acromegaly, the serum insulin-like growth factor-I (IGF-I) levels remain uncontrolled in 35% of patients. Combined therapy with octreotide LAR and cabergoline has been reported to normalize IGF-I levels in 42-56% of Caucasian patients with acromegaly. However, it remains to be clarified whether combination therapy is effective in Japanese patients and on tumor shrinkage. We conducted a retrospective study on combined therapy in patients with octreotide-resistant acromegaly. Ten patients with acromegaly who showed octreotide-resistance were enrolled in this study. Cabergoline was added in doses of 0.25-2.0mg/week. Serum GH and IGF-I levels and tumor volume were assessed before and after treatment, and factors correlated with effect of the combined therapy were analyzed. Although serum GH levels did not decrease, serum IGF-I levels significantly decreased by 20% after 6 months of combined therapy compared with baseline (p < 0.05). As a result, serum IGF-I levels normalized in 30% of the patients. Tumor volume after combined therapy also significantly decreased (p < 0.01). There were no correlations between the decrease of serum IGF-I levels during combined therapy and the response of GH in a bromocriptine test, random GH, IGF-I, and PRL levels, the tumor volume, and the expression of PRL and dopamine D2 receptor in the tumor. In conclusion, we demonstrated that the addition of cabergoline to octreotide LAR is a beneficial option in Japanese patients with octreotide-resistant acromegaly, irrespective of serum PRL levels and the response of GH levels in a bromocriptine test.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Cardiac risk in patients with treatment naïve, first-line medically controlled and first-line surgically cured acromegaly in comparison to matched data from the general population.

INTRODUCTION: Coronary risk factors in patients with acromegaly after first-line transsphenoidal surgery (TSS) or first-line somatostatine analogue (SSA) treatment have rarely been examined. Aim of this study was an evaluation of cardiovascular risk factors and left ventricular hypertrophy (LVH) in 3 different patient groups with treatment naïve, active (ACT), first-line medically controlled (MED) and first-line surgically treated (SUR) acromegaly and a calculation of the Framingham Weibull Risk Score (FS). DESIGN: Retrospective comparative matched case-control study. PATIENTS & METHODS: 40 acromegalic patients (cases aged 45-74 years, 23 men) were matched with respect to age and gender to 200 controls from the general population. 13 patients had treatment-naïve acromegaly (ACT), 12 patients were SSA treated (MED) and 15 patients were operated by TSS (SUR). Coronary risk factors were assessed after 12 months of treatment by interviews and direct laboratory measurements. Only patients normalized for IGF-I in MED and SUR group were included. FS and odds ratios (OR) from multiple conditional logistic regression (matched for age and gender, adjusted for BMI) were calculated. RESULTS: Compared to matched controls ACT patients had higher HbA1c levels (6.9±1.4 vs. 5.5±0.7% (p<0.0001)) and an increased prevalence of left ventricular hypertrophy (LVH) (30.8 vs. 3.2% (p=0.007). MED and SUR groups were similar for gender, age, disease duration and IGF-I levels at diagnosis. Compared to matched controls, MED patients had a significantly increased diastolic blood pressure (89±9 vs. 79±11 mmHg (p=0.001), prevalence of LVH (41.7 vs. 1.7% (p<0.0001), prevalence of diabetes mellitus (33.3 vs. 10.0% (p=0.03)), higher HbA1c levels (6.8±1.3 vs. 5.5±0.7% (p=0.0005)) and a higher FS (21.2±9.7 vs. 12.4±7.7% (p=0.002), OR 1.11 [1.02-1.21] (p=0.01)) while in the SUR group only higher prevalences of LVH (40.0 vs. 4.1% (p<0.0001)) and HbA1c levels (6.4±1.2 vs. 5.5±0.8% (p=0.006)) were found compared to controls. CONCLUSION: When comparing treatment naive, medically treated and surgically cured patients with acromegaly to age- and gender-matched subjects from the general population, we have found an increased cardiovascular risk in patients at 12 months after first-line SSA treatment but not in patients after first-line surgery.

Automated image analysis of hand radiographs reveals widened joint spaces in patients with long-term control of acromegaly: relation to disease activity and symptoms.

OBJECTIVE: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in patients with long-term cure of acromegaly. The late effects of acromegaly on hand joints have not been characterized. Therefore, the objective of the current study was to assess joint space widths (JSWs) of hand joints in patients with long-term control of acromegaly and to identify factors associated with JSW. METHODS: A cross-sectional study was carried out in 89 patients (age 58 ± 12 years, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms (age 46 ± 12 years, 42% women). Radiological JSWs of individual hand joints were measured by automated image analysis. RESULTS: Patients had wider mean joint spaces than controls: metacarpo-phalangeal (MCP) joints were ~24%, proximal interphalangeal joints ~21%, and distal interphalangeal joints were ~20% wider (patients vs controls; P < 0.001 for all joints). Mean JSW exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF1 and GH concentrations at diagnosis were associated with larger JSWs (adjusted ß for pretreatment GH in tertiles: 0.09 (95% confidence interval (CI) 0.03-1.84) and for IGF1 in tertiles: 0.14 (95% CI 0.05-0.23) at the MCP joints in acromegalic patients. In male patients, but not in female patients, increased JSWs were associated with more self-reported pain (P = 0.02). CONCLUSIONS: Using a new semi-automated image analysis of hand radiographs, acromegalic patients with long-term disease control appeared to have increased joint spaces of all hand joints. JSWs were positively related to disease activity at diagnosis, but not to duration of follow-up, suggesting irreversible cartilage hypertrophy. Irreversible cartilage hypertrophy may partly explain persisting hand complaints despite long-term disease control.

Fundamentos, objetivos del tratamiento, factores pronósticos y criterios de control / Basic principles, treatment objectives, prognostic factors and criteria for control

La acromegalia es una situación clínica que produce una serie de complicaciones y una mortalidad entre 2 y 4 veces superior a la esperada, sobre todo por motivo vascular. El objetivo del tratamiento, desde el punto de vista funcional, es reducir y normalizar la hipersecreción de la hormona de crecimiento (GH) por debajo de 1 ng/ml tras sobrecarga oral de glucosa, así como el control de las concentraciones del factor de crecimiento tipo insulina I (IGF-I). Desde el punto de vista anatómico, hay que extirpar el adenoma que la causa y preservar lo más posible el resto de la función hipofisaria. No están claros los factores pronósticos de curación de la enfermedad, pero los más aceptados son las concentraciones normales de GH e IGF-I tras la intervención quirúrgica. Los criterios de control tras el tratamiento han ido cambiando y se basan en concentraciones cada vez más bajas de GH tras una sobrecarga oral de glucosa, inferior a 0,1 ng/ml e IGF-I normal; no son criterios definitivos, pero la impresión es que estamos llegando a un consenso que será definitivo (AU)

Acromegaly produces a series of complications and a 2- to 3-fold increase in mortality, especially from vascular causes. From the functional point of view, the aim of treatment is to reduce growth hormone (GH) hypersecretion and return GH values to below 1 ng/ml after oral glucose load, as well as to control concentrations of insulin-like growth factor (IGF-1). From the anatomical point of view, the aim is to remove the causative adenoma while preserving the remaining pituitary function as far as possible. Factors predictive of a favorable outcome are not clearly defined but normal GH and IGF-I concentrations after surgery are the most widely accepted. Criteria for hormonal control after treatment have progressively changed and are based on increasingly lower GH values after oral glucose load, lower than 0.1 ng/ml, and normal IGF-I values. These criteria are not conclusive but a definitive consensus may soon be reached (AU)

[Acute test with subcutaneous octreotide as a predictor of the response to treatment with octreotide LAR]. / Teste agudo com octreotide subcutâneo como preditor de resposta ao tratamento com octreotide LAR.

Somatostatin analogues are frequently used to treat acromegaly. To determine the value of the acute test (AT) with subcutaneous (SC) octreotide as a predictor of the response to treatment with octreotide LAR, we analyzed data from 20 patients. For the AT, blood was drawn before and two hours after the SC administration of octreotide for measuring GH. GH levels before and after the AT were 21.9 ng/mL (2.3-143.4) and 3.1 ng/mL (0.3-61.3), respectively. Control of the disease was defined as: GH< 2.5 ng/mL and normal IGF-I anytime during treatment. Sensitivity, specificity, positive and negative predictive values of the AT were 0.9, 0.6, 0.69 and 0.86 for a reduction of 75% of the GH on the test. From our sample we conclude that a 75% reduction of the GH levels during the acute test was able to discriminate patients with a higher or lower chance of responding to treatment.

Treatment of patients with a pituitary adenoma: one clinician's experience.

The diagnosis and treatment of a patient with a pituitary adenoma or another type of pituitary lesion requires a team approach involving the neurosurgeon, endocrinologist, primary care physician, and, in some patients, an ophthalmologist and radiation therapist. The diagnosis of excessive pituitary hormone secretion and/or loss of pituitary function is based on biochemical findings and can usually be confirmed by performing blood tests, except for patients with suspected Cushing syndrome. The primary treatment of pituitary adenomas is resection, except in patients with a prolactin-producing tumor, who are most successfully treated medically with a dopamine agonist. In this article the author reviews the principles of diagnosis and treatments and offers recommendations for ideal patient care.